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, Umted States Patent ice Patented oxide catalyst in alcoholic solution, Raney nickel aluminum alloy in alkaline solution, as well as by other 2 940 996 methods, such as the use of sodium amalgam. For the most part, the substituted propionic acids are low melting X-RAY DIAGNOSTIC AGENT 5 solids and it has been found advantageous for the produc- Domenick p Bloomfield NJ assign to Schema tion of these compounds in quantity to purify the 'cinnamic acid prior to reduction in order to permit dircet iodinav v r Bloomfield a corpommm of Dela tion of the reduction product without recourse to any purification of the latter product. This is possible re- No Drawing. Filed Jan. 28, 1952, Ser. No. 268,685 10 gardless of the procedure used for reduction, since the reduced product can be isolated from the reaction mixture 3 Claims 260-521) by ether extraction. In certain cases, the reduction product in alkaline solution can be used directly for the iodination, following the removal of the catalyst and the proper This invention relates to a new group of compounds adjustment of the alkali concentration.

having X-ray contrast properties, and to a process for The iodination of the substituted propionic acids can manufacturing the same. be carried out by the use of the iodine-potassium iodide More particularly, the invention relates to polyiodimethod in alkaline solution or by the use of iodine mononated phenyl fatty acids with specific selectivity for visuchloride in dilute acid solution. Occasionally both alization of the gall bladder. Of significant interest is methods yield some diiodo compound, which is probably the concomitant visualization of the gall bladder ducts, 2,4-disubstituted. In this case, further iodination of the a property not shown by any gall bladder dyes in clinical diiodo substance will yield the triiodo compound. The

triiodo compounds of this invention have been obtained The compounds of the present invention include the as white to tan-colored crystalline compounds which are free acids and salts of the general formulas soluble in sodium bicarbonate solution and also in the OH OH usual organic solvents. The compounds of the present invention are preferably I I I admimstered 1n the form of the free acid in tablets containing the usual carriers and binders, such as starches, sugars, gums, soaps, etc. They can also be administered CH CH OOOZ -CHCH#COOH'Z as the sodium salts or calcium salts or salts with non-toxic l r organic amines such as mono-, di-, and tri-ethanolamines and the corresponding propandamines. Another very wherein R is iOWer alkyl 2 p of from 1 t0 3 Carbon suitable pharmaceutical form for the compounds of this atoms n Z is y g or an alkali or alkaline earth invention is as a suspension of either the free acids or the metal, Such as Sodium, POiaSSillm, lithium, Calcium salts, such suspension containing about 3 g. of the free g s while Z is a non-toxic mineof this acid and slightly more of the salt, corresponding to its ited group of compounds, the substances wherein R has g at ol lar weight, 2 or 3 carbons show the most favorable combination of The powdered diagnostic agent can be dissolved or susp p that non-toxicity, absence of side reactions, 40 pended in milk, water, orange juice, or other potable optimum visualiziation of the gall bladder and ducts, and li id; while the free acid an also be put up in 15 significant absence of unabsorbed dye in the colon. ampules, suspended in water containing pectin, methyl The compounds of the Present invention can be P cellulose, or kaolin or in other suspending and antacid pared from m-hydroxy benzaldehyde by the series of steps preparations. With a dose of about 3 g., a satisfactory illustrated in the following equations: X-ray picture can be obtained in about 10 to 16 hours.

( JHO on [CH3(CH2)21+1C 0120 H +OHa(CHi)nflC QN8 -r on oH=ocooH (Clinton: on (])H on I1 I I Z4 or Z I I v or -.r COOHZ' CHr-OH-OOOH OHr-(fIt-OOOH en oll-00oz (CH2)nCHt (QHflnCHs (oHmcHs wherein n is a whole number from 0 to 2. The following examples describe in greater detail, and The initial condensation of the m-hydroxy benzalde- 80 by way of illustration, satisfactory procedures for the hyde can be carried out with the alkali metal salt of the manufacture of the compounds of the invention: aliphatic acid and the acid anhydride, or the free acid may be utilized, using an equivalent amount of potassium EXAMPLE 1 acetate or triethylamine. Although by the latter procedure the yields of the substituted cinnamic acid are not comparable to those obtained by the alkali metal salt a method, such free acid procedure offers the advantage The intermediate a-methyl-m-hydroxycinnamic acid, that the alkali metal salt does not have to be prepared is prepared as follows: Two moles (244 g.) of m-hydroxye in anhydrous condition. Reduction of the cinnamic acid benzaldehyde, 222 g. (2 moles) of anhydrous sodium buto the propionic acid may be carried out by any of the tyrate and 937 g. (6 moles) of butyric anhydride are a-Ethyl-fl (2,4,6-trii0do-3-hydraxyphenyl) propionic acid known catalytic hydrogenation methods such as Raney heated at -120 with stirring for twenty hours. Afternickel catalyst in alkaline or alcoholic solution, platinum the reaction mixture is decomposed with water, the exv petroleum ether.

cess butyric acid removed by steam distillation. The

' residue is steam distilled to remove additional butyric acid and the semi-solid residue is dissolved sodium bicarbonate solution, treated with charcoal, filtered and acidified. The solid a-ethyl-3-hydroxycinnamic acid is recrystallized from water and is obtained as a white to pale yellow crystalline compound.

- Reduction of the cinnamic acid to u-ethyl-B-(3-hydroxyphenyl) propionic acid is carried out by the follow ing two methods:

U (l). Raney nickel alloy: Twenty grams of methyl-3- hydroxycinnamic acid dissolved in 2320 cc. of sodium hydroxide solution is reduced with 70 g. of Raney'nickelaluminum alloy. After filtration of the nickel, the filtrate is acidified with hydrochloric acid and extracted with ether. 1 The dried ethereal extract is evaporated to dryness and the'obtained gummy residue used without further purification in the iodination step.

(2) Catalytic hydrogenation: The a-ethyl-3-hydroxycinnamic acid is dissolved in sufiicient 5% sodium hydroxide solution to'neutralize both the carboxylic acid and phenolic groups. Raney nickel catalyst is added and the reduction run at low pressure and room temperature. After filtration of the catalyst, the alkaline solution can be used directly in the iodination employing the iodine-potassium iodide procedure, For the alternative iodination PIQCedure', the alkaline solution is acidified and the semisolid acid used directly in the iodine monochlorideprocedure. a

i w V IODINATION 7 i 1) Iodine-potassium iodide method: solution from the reduction with Raney nickel catalyst is used directly. For a 0.1 mole run, an additional 25 g. of alkali are added and the volume adjusted to 800 cc. solution of 76.2 g. of iodine and 76.2 g. of potassium iodide is made up in 400 cc. of water and the iodine-potassium iodide solution added to the hydroxy compound slowly with stirring. After the addition of the iodine solution completed, ice is added to the reaction mixture, then it. is acidified with sodium bisulfite. The filtered product is purified by solution -in sodium bicarbonate and bleaching'with sodium bisulfite and charcoal. The triiodo compound is finally recrystallized from methanol water and is obtained as a white crystalline solid.

(2) Iodine monochloride method: To ten g. of the reduction product suspended in 32.5 cc. of 6 N hydrochloric acid at 70 C., there is added a solution of 28.8 g. of iodine monochloride in 62.5 cc. of 6 N hydrochloric acid. The mixture is stirred and kept at 70 foron'e hour, then 148 cc. of water are added over a minute period. During the following five hours 295 cc. of water The alkaline In the preparation of the droxy cinnamic acid,'the anhydrous alkali metal salt procedures as well as the free acid procedure is used. The latter procedure is carried out as follows: A mixture of 244 g. (2 moles) of mhydroxy benzaldehyde, 178 g. (2 moles) of propionic acid, 780 g. (.6 moles) of propionic anhydride and 202 g. of anhydrous tn'ethylamine is heated for 25-30 hours at 120125 C. After cooling to about 60, the anhydride is decomposed cautiously with warm water and the resulting mixture steam-distilled. The steam distillation residue is then handled asdescribed for the sodium salt procedure of Example 1.

EXAMPLE 3 u-i-Propyl-fi-(2,4,6-triiodo-3-hydroxypheizyl) propzonic acid This triiodo compound is prepared by the procedure of Example 1, using isovaleric acid and isovaleric anhydride.

and 8 .2 g. of iodine monochloride are added Qn cooling,

the insoluble material crystallizes and is filtered The crude product is dissolved in sodium bicarbonate solution with heating, bleached with sodium bisulfite, treated with charcoal and filtered. Oil-acidification, a light tan product sodium propionate for the butyric-compounds of said Example 1. The triiodo compound is obtained as a white crystalline solid after recrystallization from benzenee form a compound of the formula The triiodo propionic acid is a white crystalline compound after recrystallization from benzene-petroleum ether. r

EXAMPLE 4 a-n-Propyl-B-(2,4,6trii0d03-hydroqcyphenyl) propionic acid 7 white crystalline solid which can be recrystallized from benzene-petroleum ether.

- The above procedure can be varied by employing 3-hydroxy-2,4,6-triiodo-benza1dehyde, but in such case, care must be employed in the hydrogenation of the obtained triiodo cinnamic acid to avoid splitting off .of iodine.

namic acid, and ,tri-iodinating the reduced compound to QHr-(ik-HC-O on i wherein R is an alkyl group of 1 to 3 carbon' atoms.

l 2. Process for the manufacture of a compound suitable for use as. an Xray diagnostic agent which comprises condensing 3-hydroxy benzaldehyde with sodium butyrate in thepresence of butyric anhydride, hydrogenating the aliphatic double bond of the obtained (Jr-substituted cinnamic acid, and'tri-iodinatingthereduced compound to produce a-ethyl- -(2,4,6-triiodo3-hydroxyphenyl) propionic acid. V

3. The process for preparing an acid of the formula wherein Ris an alkyl radical of 1 to v3 carbon atoms 7 which comprises heating m-hydroxybenzaldehyde with an acid anhydride of the formula (RCH CO)' O;-and1an alkali metal salt ofvanracid of they formula' RCH COOH,

2,400,433 to give a substituted propionic acid of the formula 5 2,469,415 m-HOC H CH CH(R)COOH 2,528,542

and iodinating the latter by heating it with an excess of iodine monochloride in acid solution. 517,382

References Cited in the file of this patent UNITED STATES PATENTS Natelson et all. May 14, 1946 Schwenk et a1. May 10, 1949 Papa et a1. Nov. 7, 1950 FOREIGN PATENTS Great Britain July 25, 1939 

1. PROCESS FOR THE MANUFACTURE OF COMPOUNDS SUITABLE FOR USE AS X-RAY DIAGNOSTIC AGENTS, WHICH COMPRISES CONDENSING 3-HYDROXY BENZALDEHYDE WITH A MEMBER OF THE GROUP CONSISTING OF ALIPHATIC CARBOXYLIC ACIDS HAVING FROM 3 TO 5 CARBON ATOMS AND THEIR ALKALI METAL SALTS IN THE PRESENCE OF THE ANHYDRIDE OF THE ACID, HYDROGENATING THE ALIPHATIC DOUBLE BOND OF THE OBTAINED A-SUBSTITUTED CINNAMIC ACID, AND TRI-IODINATING THE REDUCED COMPOUND TO FORM A COMPOUND OF THE FORMULA 